These recommendations are an expansion of previous
recommendations for the prevention of hepatitis C virus (HCV)
infection that focused on screening and follow-up of blood, plasma,
organ, tissue, and semen donors (CDC. Public Health Service
inter-agency guidelines for screening donors of blood, plasma,
organs, tissues, and semen for evidence of hepatitis B and
hepatitis C. MMWR 1991;40{No. RR-4};1-17). The recommendations in
this report provide broader guidelines for a) preventing
transmission of HCV; b) identifying, counseling, and testing
persons at risk for HCV infection; and c) providing appropriate
medical evaluation and management of HCV-infected persons. Based on
currently available knowledge, these recommendations were developed
by CDC staff members after consultation with experts who met in
Atlanta during July 15-17, 1998. This report is intended to serve
as a resource for health-care professionals, public health
officials, and organizations involved in the development, delivery,
and evaluation of prevention and clinical services.

INTRODUCTION

Hepatitis C virus (HCV) infection is the most common chronic
bloodborne infection in the United States. CDC staff estimate that
during the 1980s, an average of 230,000 new infections occurred
each year (CDC, unpublished data). Although since 1989 the annual
number of new infections has declined by greater than 80% to 36,000
by 1996 (1,2), data from the Third National Health and Nutrition
Examination Survey (NHANES III), conducted during 1988-1994, have
indicated that an estimated 3.9 million (1.8%) Americans have been
infected with HCV (3). Most of these persons are chronically
infected and might not be aware of their infection because they are
not clinically ill. Infected persons serve as a source of
transmission to others and are at risk for chronic liver disease or
other HCV-related chronic diseases during the first two or more
decades following initial infection.

Chronic liver disease is the tenth leading cause of death
among adults in the United States, and accounts for approximately
25,000 deaths annually, or approximately 1% of all deaths (4).
Population-based studies indicate that 40% of chronic liver disease
is HCV-related, resulting in an estimated 8,000-10,000 deaths each
year (CDC, unpublished data). Current estimates of medical and
work-loss costs of HCV-related acute and chronic liver disease are
greater than $600 million annually (CDC, unpublished data), and
HCV-associated end-stage liver disease is the most frequent
indication for liver transplantation among adults. Because most
HCV-infected persons are aged 30-49 years (3), the number of deaths
attributable to HCV-related chronic liver disease could increase
substantially during the next 10-20 years as this group of infected
persons reaches ages at which complications from chronic liver
disease typically occur.

HCV is transmitted primarily through large or repeated direct
percutaneous exposures to blood. In the United States, the relative
importance of the two most common exposures associated with
transmission of HCV, blood transfusion and injecting-drug use, has
changed over time (Figure_1) (2,5). Blood transfusion, which
accounted for a substantial proportion of HCV infections acquired
greater than 10 years ago, rarely accounts for recently acquired
infections. Since 1994, risk for transfusion-transmitted HCV
infection has been so low that CDC's sentinel counties viral
hepatitis surveillance system* has been unable to detect any
transfusion-associated cases of acute hepatitis C, although the
risk is not zero. In contrast, injecting-drug use consistently has
accounted for a substantial proportion of HCV infections and
currently accounts for 60% of HCV transmission in the United
States. A high proportion of infections continues to be associated
with injecting-drug use, but for reasons that are unclear, the
dramatic decline in incidence of acute hepatitis C since 1989
correlates with a decrease in cases among injecting-drug users.

Reducing the burden of HCV infection and HCV-related disease
in the United States requires implementation of primary prevention
activities to reduce the risk for contracting HCV infection and
secondary prevention activities to reduce the risk for liver and
other chronic diseases in HCV-infected persons. The recommendations
contained in this report were developed by reviewing currently
available data and are based on the opinions of experts. These
recommendations provide broad guidelines for a) the prevention of
transmission of HCV; b) the identification, counseling, and testing
of persons at risk for HCV infection; and c) the appropriate
medical evaluation and management of HCV-infected persons.

BACKGROUND

Prospective studies of transfusion recipients in the United
States demonstrated that rates of posttransfusion hepatitis in the
1960s exceeded 20% (6). In the mid-1970s, available diagnostic
tests indicated that 90% of posttransfusion hepatitis was not
caused by hepatitis A or hepatitis B viruses and that the move to
all-volunteer blood donors had reduced risks for posttransfusion
hepatitis to 10% (7-9). Although non-A, non-B hepatitis (i.e.,
neither type A nor type B) was first recognized because of its
association with blood transfusion, population-based sentinel
surveillance demonstrated that this disease accounted for 15%-20%
of community-acquired viral hepatitis in the United States (5).
Discovery of HCV by molecular cloning in 1988 indicated that non-A,
non-B hepatitis was primarily caused by HCV infection (5,10-14).

Epidemiology
Demographic Characteristics

HCV infection occurs among persons of all ages, but the
highest incidence of acute hepatitis C is found among persons aged
20-39 years, and males predominate slightly (5). African Americans
and whites have similar incidence of acute disease; persons of
Hispanic ethnicity have higher rates. In the general population,
the highest prevalence rates of HCV infection are found among
persons aged 30-49 years and among males (3). Unlike the
racial/ethnic pattern of acute disease, African Americans have a
substantially higher prevalence of HCV infection than do whites
(Figure_2).

Prevalence of HCV Infection in Selected Populations in the United
States

The greatest variation in prevalence of HCV infection occurs
among persons with different risk factors for infection (15)
(Table_1).
Highest prevalence of infection is found among those with large
or repeated direct percutaneous exposures to blood (e.g.,
injecting-drug users, persons with hemophilia who were treated with
clotting factor concentrates produced before 1987, and recipients
of transfusions from HCV-positive donors) (12,13,16-22). Moderate
prevalence is found among those with frequent but smaller direct
percutaneous exposures (e.g., long-term hemodialysis patients)
(23). Lower prevalence is found among those with inapparent
percutaneous or mucosal exposures (e.g., persons with evidence of
high-risk sexual practices) (24-28) or among those with small,
sporadic percutaneous exposures (e.g., health-care workers)
(29-33). Lowest
prevalence of HCV infection is found among those with
no high-risk characteristics (e.g., volunteer blood donors) (34;
personal communication, RY Dodd, Ph.D., Head, Transmissible
Diseases Department, Holland Laboratory, American Red Cross,
Rockville, MD, July 1998). The estimated prevalence of persons with
different risk factors and characteristics also varies widely in
the U.S. population (Table_1) (3; 35-39; CDC, unpublished
data).

Transmission Modes

Most risk factors associated with transmission of HCV in the
United States were identified in case-control studies conducted
during 1978-1986 (40,41). These risk factors included blood
transfusion, injecting-drug use, employment in patient care or
clinical laboratory work, exposure to a sex partner or household
member who has had a history of hepatitis, exposure to multiple sex
partners, and low socioeconomic level. These studies reported no
association with military service or exposures resulting from
medical, surgical, or dental procedures, tattooing, acupuncture,
ear piercing, or foreign travel. If transmission from such
exposures does occur, the frequency might be too low to detect.

Transfusions and Transplants. Currently, HCV is rarely
transmitted by blood transfusion. During 1985-1990, cases of
transfusion-associated non-A, non-B hepatitis declined by greater
than 50% because of screening policies that excluded donors with
human immunodeficiency virus (HIV) infection and donors with
surrogate markers for non-A, non-B hepatitis (5,42). By 1990, risk
for transfusion-associated HCV infection was approximately
1.5%/recipient or approximately 0.02%/unit transfused (42). During
May 1990, routine testing of donors for evidence of HCV infection
was initiated, and during July 1992, more sensitive -- multiantigen

testing was implemented, reducing further the risk for infection
to 0.001%/ unit transfused (43).

Receipt of clotting factor concentrates prepared from plasma
pools posed a high risk for HCV infection (44) until effective
procedures to inactivate viruses, including HCV, were introduced
during 1985 (Factor VIII) and 1987 (Factor IX). Persons with
hemophilia who were treated with products before inactivation of
those products have prevalence rates of HCV infection as high as
90% (20-22). Although plasma derivatives (e.g., albumin and immune
globulin {IG} for intramuscular {IM} administration) have not been
associated with transmission of HCV infection in the United States,
intravenous (IV) IG that was not virally inactivated was the source
of one outbreak of hepatitis C during 1993-1994 (45,46). Since
December 1994, all IG products -- IV and IM -- commercially
available in the United States must undergo an inactivation
procedure or be negative for HCV RNA (ribonucleic acid) before
release.

Transplantation of organs (e.g., heart, kidney, or liver) from
infectious donors to the organ recipient also carried a high risk
for transmitting HCV infection before donor screening (47,48).
Limited studies of recipients of transplanted tissue have
implicated transmission of HCV only from nonirradiated bone tissue
of unscreened donors (49,50). As with blood-donor screening, use of
anti-HCV-negative organ and tissue donors has virtually eliminated
risks for HCV transmission from transplantation.

Injecting and Other Illegal Drug Use. Although the number of
cases of acute hepatitis C among injecting-drug users has declined
dramatically since 1989, both incidence and prevalence of HCV
infection remain high in this group (51,52). Injecting-drug use
currently accounts for most HCV transmission in the United States,
and has accounted for a substantial proportion of HCV infections
during past decades (2,5,53). Many persons with chronic HCV
infection might have acquired their infection 20-30 years ago as a
result of limited or occasional illegal drug injecting.
Injecting-drug use leads to HCV transmission in a manner similar to
that for other bloodborne pathogens (i.e., through transfer of
HCV-infected blood by sharing syringes and needles either directly
or through contamination of drug preparation equipment) (54,55).
However, HCV infection is acquired more rapidly after initiation of
injecting than other viral infections (i.e., hepatitis B virus
{HBV} and HIV), and rates of HCV infection among young
injecting-drug users are four times higher than rates of HIV
infection (19). After 5 years of injecting, as many as 90% of users
are infected with HCV. More rapid acquisition of HCV infection
compared with other viral infections among injecting-drug users is
likely caused by high prevalence of chronic HCV infection among
injecting-drug users, which results in a greater likelihood of
exposure to an HCV-infected person.

A study conducted among volunteer blood donors in the United
States documented that HCV infection has been independently
associated with a history of intranasal cocaine use (56). (The mode
of transmission could be through sharing contaminated straws.) Data
from NHANES III indicated that 14% of the general population have
used cocaine at least once (CDC, unpublished data). Although NHANES
III data also indicated that cocaine use was associated with HCV
infection, injecting-drug use histories were not ascertained. Among
patients with acute hepatitis C identified in CDC's sentinel
counties viral hepatitis surveillance system since 1991, intranasal
cocaine use in the absence of injecting-drug use was uncommon (2).
Thus, at least in the recent past, intranasal cocaine use rarely
appears to have contributed to transmission. Until more data are
available, whether persons with a history of noninjecting illegal
drug use alone (e.g., intranasal cocaine use) are likely to be
infected with HCV remains unknown.

Nosocomial and Occupational Exposures. Nosocomial transmission
of HCV is possible if infection-control techniques or disinfection
procedures are inadequate and contaminated equipment is shared
among patients. Although reports from other countries do document
nosocomial HCV transmission (57-59), such transmission rarely has
been reported in the United States (60), other than in chronic
hemodialysis settings (61). Prevalence of antibody to HCV
(anti-HCV) positivity among chronic hemodialysis patients averages
10%, with some centers reporting rates greater than 60% (23). Both
incidence and prevalence studies have documented an association
between anti-HCV positivity and increasing years on dialysis,
independent of blood transfusion (62,63). These studies, as well as
investigations of dialysis-associated outbreaks of hepatitis C
(64), indicate that HCV transmission might occur among patients in
a hemodialysis center because of incorrect implementation of
infection-control practices, particularly sharing of medication
vials and supplies (65).

Health-care, emergency medical (e.g., emergency medical
technicians and paramedics), and public safety workers (e.g.,
fire-service, law-enforcement, and correctional facility personnel)
who have exposure to blood in the workplace are at risk for being
infected with bloodborne pathogens. However, prevalence of HCV
infection among health-care workers, including orthopedic, general,
and oral surgeons, is no greater than the general population,
averaging 1%-2%, and is 10 times lower than that for HBV infection
(29-33). In a single study that evaluated risk factors for
infection, a history of unintentional needle-stick injury was the
only occupational risk factor independently associated with HCV
infection (66).

The average incidence of anti-HCV seroconversion after
unintentional needle sticks or sharps exposures from an
HCV-positive source is 1.8% (range: 0%-7%) (67-70), with one study
reporting that transmission occurred only from hollow-bore needles
compared with other sharps (69). A study from Japan reported an
incidence of HCV infection of 10% based on detection of HCV RNA by
reverse transcriptase polymerase chain reaction (RT-PCR) (70).
Although no incidence studies have documented transmission
associated with mucous membrane or nonintact skin exposures,
transmission of HCV from blood splashes to the conjunctiva have
been described (71,72).

The risk for HCV transmission from an infected health-care
worker to patients appears to be very low. One published report
exists of such transmission during performance of exposure-prone
invasive procedures (73). That report, from Spain, described HCV
transmission from a cardiothoracic surgeon to five patients, but
did not identify factors that might have contributed to
transmission. Although factors (e.g., virus titer) might be related
to transmission of HCV, no methods exist currently that can
reliably determine infectivity, nor do data exist to determine
threshold concentration of virus required for transmission.

Percutaneous Exposures in Other Settings. In other countries,
HCV infection has been associated with folk medicine practices,
tattooing, body piercing, and commercial barbering (74-81).
However, in the United States, case-control studies have reported
no association between HCV infection and these types of exposures
(40,41). In addition, of patients with acute hepatitis C who were
identified in CDC's sentinel counties viral hepatitis surveillance
system during the past 15 years and who denied a history of
injecting-drug use, only 1% reported a history of tattooing or ear
piercing, and none reported a history of acupuncture (41; CDC,
unpublished data). Among injecting-drug users, frequency of
tattooing and ear piercing also was uncommon (3%).

Although any percutaneous exposure has the potential for
transferring infectious blood and potentially transmitting
bloodborne pathogens (i.e., HBV, HCV, or HIV), no data exist in the
United States indicating that persons with exposures to tattooing
and body piercing alone are at increased risk for HCV infection.
Further studies are needed to determine if these types of exposures
and settings in which they occur (e.g., correctional institutions,
unregulated commercial establishments), are risk factors for HCV
infection in the United States.

Sexual Activity. Case-control studies have reported an
association between exposure to a sex contact with a history of
hepatitis or exposure to multiple sex partners and acquiring
hepatitis C (40,41). In addition, 15%-20% of patients with acute
hepatitis C who have been reported to CDC's sentinel counties
surveillance system, have a history of sexual exposure in the
absence of other risk factors. Two thirds of these have an
anti-HCV-positive sex partner, and one third reported greater than
2 partners in the 6 months before illness (2).

In contrast, a low prevalence of HCV infection has been
reported by studies of long-term spouses of patients with chronic
HCV infection who had no other risk factors for infection. Five of
these studies have been conducted in the United States, involving
30-85 partners each, in which average prevalence of HCV infection
was 1.5% (range: 0% to 4.4%) (56,82-85). Among partners of persons
with hemophilia coinfected with HCV and HIV, two studies have
reported an average prevalence of HCV infection of 3% (83,86). One
additional study evaluated potential transmission of HCV between
sexually transmitted disease (STD) clinic patients, who denied
percutaneous risk factors, and their steady partners (28).
Prevalence of HCV infection among male patients with an
anti-HCV-positive
female partner (7%) was no different than that among males
with a negative female partner (8%). However, female patients with
an anti-HCV-positive partner were almost fourfold more likely to
have HCV infection than females with a negative male partner (10%
versus 3%, respectively). These data indicate that, similar to
other bloodborne viruses, sexual transmission of HCV from males to
females might be more efficient than from females to males.

Among persons with evidence of high-risk sexual practices
(e.g., patients attending STD clinics and female prostitutes) who
denied a history of injecting-drug use, prevalence of anti-HCV has
been found to average 6% (range: 1%-10%) (24-28,87). Specific
factors associated with anti-HCV positivity for both heterosexuals
and men who have sex with men (MSM) included greater numbers of sex
partners, a history of prior STDs, and failure to use a condom.
However, the number of partners associated with infection risk
varied among studies, ranging from greater than 1 partner in the
previous month to greater than 50 in the previous year. In studies
of other populations, the number of partners associated with HCV
infection also varied, ranging from greater than 2 partners in the
6 months before illness for persons with acute hepatitis C (41), to
greater than or equal to 5 partners/year for HCV-infected volunteer
blood donors (56), to greater than or equal to 10 lifetime partners
for HCV-infected persons in the general population (3).

Only one study has documented an association between HCV
infection and MSM activity (28), and at least in STD clinic
settings, the prevalence rate of HCV infection among MSM generally
has been similar to that of heterosexuals. Because sexual
transmission of bloodborne viruses is recognized to be more
efficient among MSM compared with heterosexual men and women, why
HCV infection rates are not substantially higher among MSM compared
with heterosexuals is unclear. This observation and the low
prevalence of HCV infection observed among long-term spouses of
persons with chronic HCV infection have raised doubts regarding the
importance of sexual activity in transmission of HCV.
Unacknowledged percutaneous risk factors (i.e., illegal
injecting-drug use) might contribute to increased risk for HCV
infection among persons with high-risk sexual practices.

Although considerable inconsistencies exist among studies,
data indicate overall that sexual transmission of HCV appears to
occur, but that the virus is inefficiently spread through this
manner. More data are needed to determine the risk for, and factors
related to, transmission of HCV between long-term steady partners
as well as among persons with high-risk sexual practices, including
whether other STDs promote transmission of HCV by influencing viral
load or modifying mucosal barriers.

Household Contact. Case-control studies also have reported an
association between nonsexual household contact and acquiring
hepatitis C (40,41). The presumed mechanism of transmission is
direct or inapparent percutaneous or permucosal exposure to
infectious blood or body fluids containing blood. In a recent
investigation in the United States, an HCV-infected mother
transmitted HCV to her hemophilic child during performance of home
infusion therapy, presumably when she had an unintentional needle
stick and subsequently used the contaminated needle in the child
(88).

Although prevalence of HCV infection among nonsexual household
contacts of persons with chronic HCV infection in the United States
is unknown, HCV transmission to such contacts is probably uncommon.
In studies from other countries of nonsexual household contacts of
patients with chronic hepatitis C, average anti-HCV prevalence was
4% (15). Although infected contacts in these studies reported no
other commonly recognized risk factors for hepatitis C, most of
these studies were done in countries where exposures commonly
experienced in the past from contaminated equipment used in
traditional and nontraditional medical procedures might have
contributed to clustering of HCV infections in families (75,76,79).

Perinatal. The average rate of HCV infection among infants
born to HCV-positive, HIV-negative women is 5%-6% (range: 0%-25%),
based on detection of anti-HCV and HCV RNA, respectively (89-101).
The average infection rate for infants born to women coinfected
with HCV and HIV is higher -- 14% (range: 5%-36%) and 17%, based on
detection of anti-HCV and HCV RNA, respectively (90,96,98-104). The
only factor consistently found to be associated with transmission
has been the presence of HCV RNA in the mother at the time of
birth. Although two studies of infants born to HCV-positive,
HIV-negative women reported an association with titer of HCV RNA,
each study reported a different level of HCV RNA related to
transmission (92,93). Studies of HCV/HIV-coinfected women more
consistently have indicated an association between virus titer and
transmission of HCV (102).

Data regarding the relationship between delivery mode and HCV
transmission are limited and presently indicate no difference in
infection rates between infants delivered vaginally compared with
cesarean-delivered infants. The transmission of HCV infection
through breast milk has not been documented. In the studies that
have evaluated breastfeeding in infants born to HCV-infected women,
average rate of infection was 4% in both breastfed and bottle-fed
infants (95,96,99,100,105,106).

Diagnostic criteria for perinatal HCV infection have not been
established. Various anti-HCV patterns have been observed in both
infected and uninfected infants of anti-HCV-positive mothers.
Passively acquired maternal antibody might persist for months, but
probably not for greater than 12 months. HCV RNA can be detected as
early as 1 to 2 months.

Persons with No Recognized Source for Their Infection. Recent
studies have demonstrated that injecting-drug use currently
accounts for 60% of HCV transmission in the United States (2).
Although the role of sexual activity in transmission of HCV remains
unclear, less than or equal to 20% of persons with HCV infection
report sexual exposures (i.e., exposure to an infected sexual
partner or to multiple partners) in the absence of percutaneous
risk factors (2). Other known exposures (occupational,
hemodialysis, household, perinatal) together account for
approximately 10% of infections. Thus, a potential risk factor can
be identified for approximately 90% of persons with HCV infection.
In the remaining 10%, no recognized source of infection can be
identified, although most persons in this category are associated
with low socioeconomic level. Although low socioeconomic level has
been associated with several infectious diseases and might be a
surrogate for high-risk exposures, its nonspecific nature makes
targeting prevention measures difficult.

Screening and Diagnostic Tests
Serologic Assays

The only tests currently approved by the U.S. Food and Drug
Administration (FDA) for diagnosis of HCV infection are those that
measure anti-HCV (Table_2) (107). These tests detect anti-HCV
in
greater than or equal to 97% of infected patients, but do not
distinguish between acute, chronic, or resolved infection. As with
any screening test, positive predictive value of enzyme immunoassay
(EIA) for anti-HCV varies depending on prevalence of infection in
the population and is low in populations with an HCV-infection
prevalence of less than 10% (1,34). Supplemental testing with a
more specific assay (i.e., recombinant immunoblot assay {RIBATM})
of a specimen with a positive EIA result prevents reporting of
false-positive results, particularly in settings where asymptomatic
persons are being tested.

Supplemental test results might be reported as positive,
negative, or indeterminate. An anti-HCV-positive person is defined
as one whose serologic results are EIA-test-positive and
supplemental-test-positive. Persons with a negative EIA test result
or a positive EIA and a negative supplemental test result are
considered uninfected, unless other evidence exists to indicate HCV
infection (e.g., abnormal ALT levels in immunocompromised persons
or persons with no other etiology for their liver disease).
Indeterminate supplemental test results have been observed in
recently infected persons who are in the process of seroconversion,
as well as in persons chronically infected with HCV. Indeterminate
anti-HCV results also might indicate a false-positive result,
particularly in those persons at low risk for HCV infection.

Nucleic Acid Detection

The diagnosis of HCV infection also can be made by
qualitatively detecting HCV RNA using gene amplification techniques
(e.g., RT-PCR) (Table_2) (108). HCV RNA can be detected in
serum or
plasma within 1-2 weeks after exposure to the virus and weeks
before the onset of alanine aminotransferase (ALT) elevations or
the appearance of anti-HCV. Rarely, detection of HCV RNA might be
the only evidence of HCV infection. Although RT-PCR assay kits for
HCV RNA are available for research purposes from various
manufacturers of diagnostic reagents, none have been approved by
FDA. In addition, numerous laboratories perform RT-PCR using
in-house laboratory methods and reagents.

Although not FDA-approved, RT-PCR assays for HCV infection are
used commonly in clinical practice. Most RT-PCR assays have a lower
limit of detection of 100-1,000 viral genome copies/mL. With
adequate optimization of RT-PCR assays, 75%-85% of persons who are
anti-HCV-positive and greater than 95% of persons with acute or
chronic hepatitis C will test positive for HCV RNA. Some
HCV-infected persons might be only intermittently HCV RNA-positive,
particularly those with acute hepatitis C or with end-stage liver
disease caused by hepatitis C. To minimize false-negative results,
serum must be separated from cellular components within 2-4 hours
after collection, and preferably stored frozen at -20 C or -70 C
(109). If shipping is required, frozen samples should be protected
from thawing. Because of assay variability, rigorous quality
assurance and control should be in place in clinical laboratories
performing this assay, and proficiency testing is recommended.

Quantitative assays for measuring the concentration (titer) of
HCV RNA have been developed and are available from commercial
laboratories (110), including a quantitative RT-PCR (Amplicor HCV
MonitorTM, Roche Molecular Systems, Branchburg, New Jersey) and a
branched DNA (deoxyribonucleic acid) signal amplification assay
(QuantiplexTM HCV RNA Assay {bDNA}, Chiron Corp., Emeryville,
California) (Table_2). These assays also are not FDA-approved,
and
compared with qualitative RT-PCR assays, are less sensitive with
lower limits of detection of 500 viral genome copies/mL for the
Amplicor HCV MonitorTM to 200,000 genome equivalents/mL for the
QuantiplexTM HCV RNA Assay (111). In addition, they each use a
different standard, which precludes direct comparisons between the
two assays. Quantitative assays should not be used as a primary
test to confirm or exclude diagnosis of HCV infection or to monitor
the endpoint of treatment. Patients with chronic hepatitis C
generally circulate virus at levels of 105-107 genome copies/mL.
Testing for level of HCV RNA might help predict likelihood of
response to antiviral therapy, although sequential measurement of
HCV RNA levels has not proven useful in managing patients with
hepatitis C.

At least six different genotypes and greater than 90 subtypes
of HCV exist (112). Approximately 70% of HCV-infected persons in
the United States are infected with genotype 1, with frequency of
subtype 1a predominating over subtype 1b. Different nucleic acid
detection methods are available commercially to group isolates of
HCV, based on genotypes and subtypes (113). Evidence is limited
regarding differences in clinical features, disease outcome, or
progression to cirrhosis or hepatocellular carcinoma (HCC) among
persons with different genotypes. However, differences do exist in
responses to antiviral therapy according to HCV genotype. Rates of
response in patients infected with genotype 1 are substantially
lower than in patients with other genotypes, and treatment regimens
might differ on the basis of genotype. Thus, genotyping might be
warranted among persons with chronic hepatitis C who are being
considered for antiviral therapy.

Clinical Features and Natural History
Acute HCV Infection

Persons with acute HCV infection typically are either
asymptomatic or have a mild clinical illness; 60%-70% have no
discernible symptoms; 20%-30% might have jaundice; and 10%-20%
might have nonspecific symptoms (e.g., anorexia, malaise, or
abdominal pain) (13,114,115). Clinical illness in patients with
acute hepatitis C who seek medical care is similar to that of other
types of viral hepatitis, and serologic testing is necessary to
determine the etiology of hepatitis in an individual patient. In
less than or equal to 20% of these patients, onset of symptoms
might precede anti-HCV seroconversion. Average time period from
exposure to symptom onset is 6-7 weeks (116-118), whereas average
time period from exposure to seroconversion is 8-9 weeks (114;
personal communication, HJ Alter, M.D., Chief, Department of
Transfusion Medicine, Clinical Center, National Institutes of
Health, Bethesda, MD, September 1998). Anti-HCV can be detected in
80% of patients within 15 weeks after exposure, in greater than or
equal to 90% within 5 months after exposure, and in greater than or
equal to 97% by 6 months after exposure (14,114). Rarely,
seroconversion might be delayed until 9 months after exposure
(14,119).

The course of acute hepatitis C is variable, although
elevations in serum ALT levels, often in a fluctuating pattern, are
its most characteristic feature. Normalization of ALT levels might
occur and suggests full recovery, but this is frequently followed
by ALT elevations that indicate progression to chronic disease
(14). Fulminant hepatic failure following acute hepatitis C is rare
(120,121).

Chronic HCV Infection

After acute infection, 15%-25% of persons appear to resolve
their infection without sequelae as defined by sustained absence of
HCV RNA in serum and normalization of ALT levels (122; personal
communication, LB Seeff, M.D., Senior Scientist {Hepatitis C},
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD, July 1998). Chronic
HCV infection develops in most persons (75%-85%)(14,122-124), with
persistent or fluctuating ALT elevations indicating active liver
disease developing in 60%-70% of chronically infected persons
(12-15,116,122-124). In the remaining 30%-40% of chronically
infected
persons, ALT levels are normal. No clinical or epidemiologic
features among patients with acute infection have been found to be
predictive of either persistent infection or chronic liver disease.
Moreover, various ALT patterns have been observed in these patients
during follow-up, and patients might have prolonged periods
(greater than or equal to 12 months) of normal ALT activity even
though they have histologic-confirmed chronic hepatitis (14). Thus,
a single ALT determination cannot be used to exclude ongoing
hepatic injury, and long-term follow-up of patients with HCV
infection is required to determine their clinical outcome or
prognosis.

The course of chronic liver disease is usually insidious,
progressing at a slow rate without symptoms or physical signs in
the majority of patients during the first two or more decades after
infection. Frequently, chronic hepatitis C is not recognized until
asymptomatic persons are identified as HCV-positive during
blood-donor screening, or elevated ALT levels are detected during
routine physical examinations. Most studies have reported that
cirrhosis develops in 10%-20% of persons with chronic hepatitis C
over a period of 20-30 years, and HCC in 1%-5%, with striking
geographic variations in rates of this disease (124-128). However,
when cirrhosis is established, the rate of development of HCC might
be as high as 1%-4%/year. In contrast, a study of greater than 200
women 17 years after they received HCV-contaminated Rh factor IG
reported that only 2.4% had evidence of cirrhosis and none had died
(129). Thus, longer term follow-up studies are needed to assess
lifetime consequences of chronic hepatitis C, particularly among
those who acquired their infection at young ages.

Although factors predicting severity of liver disease have not
been well-defined, recent data indicate that increased alcohol
intake, being aged greater than 40 years at infection, and being
male are associated with more severe liver disease (130). In
particular, among persons with alcoholic liver disease and HCV
infection, liver disease progresses more rapidly; among those with
cirrhosis, a higher risk for development of HCC exists (131).
Furthermore, even intake of moderate amounts (greater than 10
g/day) of alcohol in patients with chronic hepatitis C might
enhance disease progression. More severe liver injury observed in
persons with alcoholic liver disease and HCV infection possibly is
attributable to alcohol-induced enhancement of viral replication or
increased susceptibility of cells to viral injury. In addition,
persons who have chronic liver disease are at increased risk for
fulminant hepatitis A (132).

Extrahepatic manifestations of chronic HCV infection are
considered to be of immunologic origin and include
cryoglobulinemia, membranoproliferative glomerulonephritis, and
porphyria cutanea tarda (131). Other extrahepatic conditions have
been reported, but definitive associations of these conditions with
HCV infection have not been established. These include seronegative
arthritis, Sjogren syndrome, autoimmune thyroiditis, lichen planus,
Mooren corneal ulcers, idiopathic pulmonary fibrosis (Hamman-Rich
syndrome), polyarteritis nodosa, aplastic anemia, and B-cell
lymphomas.

Clinical Management and Treatment

HCV-positive patients should be evaluated for presence and
severity of chronic liver disease (133). Initial evaluation for
presence of disease should include multiple measurements of ALT at
regular intervals, because ALT activity fluctuates in persons with
chronic hepatitis C. Patients with chronic hepatitis C should be
evaluated for severity of their liver disease and for possible
treatment (133-135).

Antiviral therapy is recommended for patients with chronic
hepatitis C who are at greatest risk for progression to cirrhosis
(133). These persons include anti-HCV-positive patients with
persistently elevated ALT levels, detectable HCV RNA, and a liver
biopsy that indicates either portal or bridging fibrosis or at
least moderate degrees of inflammation and necrosis.

In patients with less severe histologic changes, indications
for treatment are less clear, and careful clinical follow-up might
be an acceptable alternative to treatment with antiviral therapy
(e.g., interferon) because progression to cirrhosis is likely to be
slow, if it occurs at all. Similarly, patients with compensated
cirrhosis (without jaundice, ascites, variceal hemorrhage, or
encephalopathy) might not benefit from interferon therapy. Careful
assessment should be made, and the risks and benefits of therapy
should be thoroughly discussed with the patient.

Patients with persistently normal ALT values should not be
treated with interferon outside of clinical trials because
treatment might actually induce liver enzyme abnormalities (136).
Patients with advanced cirrhosis who might be at risk for
decompensation with therapy and pregnant women also should not be
treated. Interferon treatment is not FDA-approved for patients aged
less than 18 years, and more data are needed regarding treatment of
persons aged less than 18 years or greater than 60 years. Treatment
of patients who are drinking excessive amounts of alcohol or who
are injecting illegal drugs should be delayed until these behaviors
have been discontinued for greater than or equal to 6 months.
Contraindications to treatment with interferon include major
depressive illness, cytopenias, hyperthyroidism, renal
transplantation, and evidence of autoimmune disease.

Most clinical trials of treatment for chronic hepatitis C have
been conducted using alpha-interferon (134,135,137,138). When the
recommended regimen of 3 million units administered subcutaneously
3 times/week for 12 months is used, approximately 50% of treated
patients have normalization of serum ALT activity (biochemical
response), and 33% have a loss of detectable HCV RNA in serum
(virologic response) at the end of therapy. However, greater than
or equal to 50% of these patients relapse when therapy is stopped.
Thus, 15%-25% have a sustained response as measured by testing for
ALT and HCV RNA greater than or equal to 1 years after therapy is
stopped, many of whom also have histologic improvement. For
patients who do not respond by the end of therapy, retreatment with
a standard dose of interferon is rarely effective. Patients who
have persistently abnormal ALT levels and detectable HCV RNA in
serum after 3 months of interferon are unlikely to respond to
treatment, and interferon treatment should be discontinued. These
persons might be considered for participation in clinical trials of
alternative treatments. Decreased interferon response rates (less
than 15%) have been found in patients with higher serum HCV RNA
titers and HCV genotype 1 (the most common strain of HCV in the
United States); however, treatment should not be withheld based
solely on these findings.

Therapy for hepatitis C is a rapidly changing area of clinical
practice. Combination therapy with interferon and ribavirin, a
nucleoside analogue, is now FDA-approved for treatment of chronic
hepatitis C in patients who have relapsed following interferon
treatment and might be approved soon for patients who have not been
treated previously. Studies of patients treated with a combination
of ribavirin and interferon have demonstrated a substantial
increase in sustained response rates, reaching 40%-50%, compared
with response rates of 15%-25% with interferon alone (139,140).
However, as with interferon alone, combination therapy in patients
with genotype 1 is not as successful, and sustained response rates
among these patients are still less than 30%.

Most patients receiving interferon experience flu-like
symptoms early in treatment, but these symptoms diminish with
continued treatment. Later side effects include fatigue, bone
marrow suppression, and neuropsychiatric effects (e.g., apathy,
cognitive changes, irritability, and depression). Interferon dosage
must be reduced in 10%-40% of patients and discontinued in 5% -15%
because of severe side effects. Ribavirin can induce hemolytic
anemia and can be problematic for patients with preexisting anemia,
bone marrow suppression, or renal failure. In these patients,
combination therapy should be avoided or attempts should be made to
correct the anemia. Hemolytic anemia caused by ribavirin also can
be life-threatening for patients with ischemic heart disease or
cerebral vascular disease. Ribavirin is teratogenic, and female
patients should avoid becoming pregnant during therapy.

Other treatments, including corticosteroids, ursodiol, and
thymosin, have not been effective. High iron levels in the liver
might reduce the efficacy of interferon. Use of iron-reduction
therapy (phlebotomy or chelation) in combination with interferon
has been studied, but results have been inconclusive. Because
patients are becoming more interested in alternative therapies
(e.g., traditional Chinese medicine, antioxidants, naturopathy, and
homeopathy), physicians should be prepared to address questions
regarding these topics.

Postexposure Prophylaxis and Follow-Up

Available data regarding the prevention of HCV infection with
IG indicate that IG is not effective for postexposure prophylaxis
of hepatitis C (67,141). No assessments have been made of
postexposure use of antiviral agents (e.g., interferon) to prevent
HCV infection. Mechanisms of the effect of interferon in treating
patients with hepatitis C are poorly understood, and an established
infection might need to be present for interferon to be an
effective treatment (142). As of the publication of this report,
interferon is FDA-approved only for treatment of chronic hepatitis
C.

The immediate postexposure setting provides opportunity to
identify persons early in the course of their HCV infection.
Studies indicate that interferon treatment begun early in the
course of HCV infection is associated with a higher rate of
resolved infection (143). However, no data exist indicating that
treatment begun during the acute phase of infection is more
effective than treatment begun early during the course of chronic
HCV infection. In addition, as stated previously, interferon is not
FDA-approved for this indication. Determination of whether
treatment of HCV infection is more beneficial in the acute phase
than in the early chronic phase will require evaluation with
well-designed research protocols.

PREVENTION AND CONTROL RECOMMENDATIONS
Rationale

Reducing the burden of HCV infection and HCV-related disease
in the United States requires implementation of primary prevention
activities that reduce risks for contracting HCV infection and
secondary prevention activities that reduce risks for liver and
other chronic diseases in HCV-infected persons. In addition,
surveillance and evaluation activities are required to determine
the effectiveness of prevention programs in reducing incidence of
disease, identifying persons infected with HCV, providing
appropriate medical follow-up, and promoting healthy lifestyles and
behaviors.

Primary prevention activities can reduce or eliminate
potential risk for HCV transmission from a) blood, blood
components, and plasma derivatives; b) such high-risk activities as
injecting-drug use and sex with multiple partners; and c)
percutaneous exposures to blood in health care and other (i.e.,
tattooing and body piercing) settings. Immunization against HCV is
not available; therefore, identifying persons at risk but not
infected with HCV provides opportunity for counseling on how to
reduce their risk for becoming infected.

Elements of a comprehensive strategy to prevent and control
hepatitis C virus (HCV) infection and HCV-related disease

Surveillance and research to monitor disease trends and the
effectiveness of prevention activities and to develop improved
prevention methods.

Secondary prevention activities can reduce risks for chronic
disease by identifying HCV-infected persons through diagnostic
testing and by providing appropriate medical management and
antiviral therapy. Because of the number of persons with chronic
HCV infection, identification of these persons must be a major
focus of current prevention programs. Identification of persons at
risk for HCV infection provides opportunity for testing to
determine their infection status, medical evaluation to determine
their disease status if infected, and antiviral therapy, if
appropriate. Identification also provides infected persons
opportunity to obtain information concerning how they can prevent
further harm to their liver and prevent transmitting HCV to others.

Factors for consideration when making decisions regarding
development and implementation of preventive services for a
particular disease include the public health importance of the
disease, the availability of appropriate diagnostic tests, and the
effectiveness of available preventive and therapeutic
interventions. However, identification of persons at risk for HCV
infection must take into account not only the benefits but also the
limitations and drawbacks associated with such efforts. Hepatitis
C is a disease of major public health importance, and suitable and
accurate diagnostic tests as well as behavioral and therapeutic
interventions are available. Counseling and testing can prevent
disease transmission and progression through reducing high-risk
practices (e.g., injecting-drug use and alcohol intake). However,
the degree to which persons will change their high-risk practices
based on knowing their test results is not known, and possible
adverse consequences of testing exist, including disclosure of test
results to others that might result in disrupted personal
relationships and possible discriminatory action (e.g., loss of
employment, insurance, and educational opportunities). Antiviral
treatment is also available, and treatment guidelines have been
developed. Such treatment is beneficial for many patients, although
sustained response rates and mode of delivery are currently less
than ideal.

Persons at risk for HCV infection who receive health-care
services in the public and private sectors should have access to
counseling and testing. Facilities that provide counseling and
testing should include services or referrals for medical evaluation
and management of persons identified as infected with HCV.
Priorities for implementing new counseling and testing programs
should be based on providing access to persons who are most likely
to be infected or who practice high-risk behaviors.

Current practices that exclude blood, plasma, organ, tissue,
or semen donors determined to be at increased risk for HCV by
history or who have serologic markers for HCV infection must be
maintained to prevent HCV transmission from transfusions and
transplants (1). Viral inactivation of clotting factor concentrates
and other products derived from human plasma, including IG
products, also must be continued, and all plasma-derived products
that do not undergo viral inactivation should be HCV RNA negative
by RT-PCR before release.

High-Risk Drug and Sexual Practices

Health-care professionals in all patient care settings
routinely should obtain a history that inquires about use of
illegal drugs (injecting and noninjecting) and evidence of
high-risk sexual practices (e.g., multiple sex partners or a
history of STDs). Primary prevention of illegal drug injecting will
eliminate the greatest risk factor for HCV infection in the United
States (144). Although consistent data are lacking regarding the
extent to which sexual activity contributes to HCV transmission,
persons having multiple sex partners are at risk for STDs (e.g.,
HIV, HBV, syphilis, gonorrhea, and chlamydia). Counseling and
education to prevent initiation of drug-injecting or high-risk
sexual practices is important, especially for adolescents. Persons
who inject drugs or who are at risk for STDs should be counseled
regarding what they can do to minimize their risk for becoming
infected or of transmitting infectious agents to others, including
need for vaccination against hepatitis B (144-148). Injecting and
noninjecting illegal drug users and sexually active MSM also should
be vaccinated against hepatitis A (149).

Prevention messages for persons with high-risk drug or sexual
practices

Persons who use or inject illegal drugs should be advised

to stop using and injecting drugs.

to enter and complete substance-abuse treatment, including
relapse-prevention programs.

if continuing to inject drugs,

to never reuse or "share" syringes, needles, water, or
drug preparation equipment; if injection equipment has
been
used by other persons, to first clean the equipment
with
bleach and water;

to use only sterile syringes obtained from a reliable
source (e.g., pharmacies);

to use a new sterile syringe to prepare and inject
drugs;

if possible, to use sterile water to prepare drugs;
otherwise to use clean water from a reliable source
(such as fresh tap water).

to use a new or disinfected container ("cooker") and
a new filter ("cotton") to prepare drugs;

to clean the injection site before injection with a
new alcohol swab; and

to safely dispose of syringes after one use.

to get vaccinated against hepatitis B and hepatitis A.

Persons who are at risk for sexually transmitted diseases should
be advised

that the surest way to prevent the spread of human
immunodeficiency virus infection and other sexually
transmitted
diseases is to have sex with only one uninfected partner or
not to
have sex at all.

to use latex condoms correctly and every time to protect
themselves and their partners from diseases spread through
sexual
activity.

to get vaccinated against hepatitis B, and if appropriate,
hepatitis A.

Counseling of persons with potential or existing illegal drug

use or high-risk sexual practices should be conducted in the
setting in which the patient is identified. If counseling services
cannot be provided on-site, patients should be referred to a
convenient community resource, or at a minimum, provided
easy-to-understand health-education material. STD and
drug-treatment clinics, correctional institutions, and HIV
counseling and testing sites should routinely provide information
concerning prevention of HCV and HBV infection in their counseling
messages. Based on the findings of multiple studies, syringe and
needle-exchange programs can be an effective part of a
comprehensive strategy to reduce the incidence of bloodborne virus
transmission and do not encourage the use of illegal drugs
(150-153).
Therefore, to reduce the risk for HCV infection among
injecting-drug users, local communities can consider implementing
syringe and needle-exchange programs.

Percutaneous Exposures to Blood in Health Care and Other Settings
Health-Care Settings

Health-care, emergency medical, and public safety workers
should be educated regarding risk for and prevention of bloodborne
infections, including the need to be vaccinated against hepatitis
B (154-156). Standard barrier precautions and engineering controls
should be implemented to prevent exposure to blood. Protocols
should be in place for reporting and follow-up of percutaneous or
permucosal exposures to blood or body fluids that contain blood.

Health-care professionals responsible for overseeing patients
receiving home infusion therapy should ensure that patients and
their families (or caregivers) are informed of potential risk for
infection with bloodborne pathogens, and should assess their
ability to use adequate infection-control practices consistently
(88). Patients and families should receive training with a
standardized curriculum that includes appropriate infection-control
procedures, and these procedures should be evaluated regularly
through home visits.

Currently, no recommendations exist to restrict professional
activities of health-care workers with HCV infection. As
recommended for all health-care workers, those who are HCV-positive
should follow strict aseptic technique and standard precautions,
including appropriate use of hand washing, protective barriers, and
care in the use and disposal of needles and other sharp instruments
(154,155).

In chronic hemodialysis settings, intensive efforts must be
made to educate new staff and reeducate existing staff regarding
hemodialysis-specific infection-control practices that prevent
transmission of HCV and other bloodborne pathogens (65,157).
Hemodialysis-center precautions are more stringent than standard
precautions. Standard precautions require use of gloves only when
touching blood, body fluids, secretions, excretions, or
contaminated items. In contrast, hemodialysis-center precautions
require glove use whenever patients or hemodialysis equipment is
touched. Standard precautions do not restrict use of supplies,
instruments, and medications to a single patient;
hemodialysis-center precautions specify that none of these items be
shared among any patients. Thus, appropriate use of
hemodialysis-center precautions should prevent transmission of HCV
among chronic hemodialysis patients, and isolation of HCV-positive
patients is not necessary or recommended.

Routine precautions for the care of all hemodialysis patients

Patients should have specific dialysis stations assigned to
them, and chairs and beds should be cleaned after each use.

Sharing among patients of ancillary supplies such as trays,
blood pressure cuffs, clamps, scissors, and other nondisposable
items should be avoided.

Nondisposable items should be cleaned or disinfected
appropriately between uses.

Medications and supplies should not be shared among patients,
and medication carts should not be used.

Medications should be prepared and distributed from a
centralized area.

Clean and contaminated areas should be separated (e.g., handling
and storage of medications and hand washing should not be done
in
the same or an adjacent area to that where used equipment or
blood
samples are handled).

Other Settings

Persons who are considering tattooing or body piercing should
be informed of potential risks of acquiring infection with
bloodborne and other pathogens through these procedures. These
procedures might be a source of infection if equipment is not
sterile or if the artist or piercer does not follow other proper
infection-control procedures (e.g., washing hands, using latex
gloves, and cleaning and disinfecting surfaces).

Testing should be offered routinely to persons most likely to
be infected with HCV who might require medical management, and
testing should be accompanied by appropriate counseling and medical
follow-up. In addition, anyone who wishes to know or is concerned
regarding their HCV-infection status should be provided the
opportunity for counseling, testing, and appropriate follow-up. The
determination of which persons at risk to recommend for routine
testing is based on various considerations, including a known
epidemiologic relationship between a risk factor and acquiring HCV
infection, prevalence of risk behavior or characteristic in the
population, prevalence of infection among those with a risk
behavior or characteristic, and the need for persons with a
recognized exposure to be evaluated for infection.

Persons who should be tested routinely for hepatitis C virus (HCV)
infection based on their risk for infection

Persons who ever injected illegal drugs, including those who
injected once or a few times many years ago and do not consider
themselves as drug users.

Persons with selected medical conditions, including

persons who received clotting factor concentrates produced
before 1987;

persons who were ever on chronic (long-term) hemodialysis;
and

persons with persistently abnormal alanine aminotransferase
levels.

Prior recipients of transfusions or organ transplants, including

persons who were notified that they received blood from a
donor who later tested positive for HCV infection;

persons who received a transfusion of blood or blood
components before July 1992; and

persons who received an organ transplant before July 1992.

Persons who should be tested routinely for HCV-infection based on
a recognized exposure

Health-care professionals in primary-care and other
appropriate settings routinely should question patients regarding
their history of injecting-drug use, and should counsel, test, and
evaluate for HCV infection, persons with such histories. Current
injecting-drug users frequently are not seen in the primary
health-care setting and might not be reached by traditional media;
therefore, community-based organizations serving these populations
should determine the most effective means of integrating
appropriate HCV information and services into their programs.

Testing persons in settings with potentially high proportions
of injecting-drug users (e.g., correctional institutions, HIV
counseling and testing sites, or drug and STD treatment programs)
might be particularly efficient for identifying HCV-positive
persons. HCV testing programs in these settings should include
counseling and referral or arrangements for medical management.
However, limited experience exists in combining HCV programs with
existing HIV, STD, or other established services for populations at
high risk for infection with bloodborne pathogens. Persons at risk
for HCV infection through limited or occasional drug use,
particularily in the remote past, might not be receptive to
receiving services in such settings as HIV counseling and testing
sites and drug and STD treatment programs. In addition, whether a
substantial proportion of this group at risk can be identified in
these settings is unknown. Studies are needed to determine the best
approaches for reaching persons who might not identify themselves
as being at risk for HCV infection.

Persons with Selected Medical Conditions

Persons with hemophilia who received clotting factor
concentrates produced before 1987 and long-term hemodialysis
patients should be tested for HCV infection. Educational efforts
directed to health-care professionals, patient organizations, and
agencies who care for these patients should emphasize the need for
these patients to know whether they are infected with HCV and
encourage testing for those who have not been tested previously.
Periodic testing of long-term hemodialysis patients for purposes of
infection control is currently not recommended (61). However,
issues surrounding prevention of HCV and other bloodborne pathogen
transmission in long-term hemodialysis settings are currently
undergoing discussion, and updating recommendations for this
setting is under development.

Persons with persistently abnormal ALT levels are often
identified in medical settings. As part of their medical work-up,
health-care professionals should test routinely for HCV infection
persons with ALT levels above the upper limit of normal on at least
two occasions. Persons with other evidence of liver disease
identified by abnormal serum aspartate aminotransferase (AST)
levels, which is common among persons with alcohol-related liver
disease, should be tested also.

Prior Recipients of Blood Transfusions or Organ Transplants

Persons who might have become infected with HCV through
transfusion of blood and blood components should be notified. Two
types of approaches should be used -- a) a targeted, or directed,
approach to identify prior transfusion recipients from donors who
tested anti-HCV positive after multiantigen screening tests were
widely implemented (July 1992 and later); and b) a general approach
to identify all persons who received transfusions before July 1992.
A targeted notification approach focuses on a specific group known
to be at risk, and will reach persons who might be unaware they
were transfused. However, because blood and blood-component donor
testing for anti-HCV before July 1992 did not include confirmatory
testing, most of these notifications would be based on donors who
were not infected with HCV because their test results were falsely
positive. A general education campaign to identify persons
transfused before July 1992 has the advantage of not being
dependent on donor testing status or availability of records, and
potentially reaches persons who received HCV-infected blood from
donors who tested falsely negative on the less sensitive serologic
test, as well as from donors before testing was available.

Persons who received blood from a donor who tested positive for
HCV infection after multiantigen screening tests were widely
implemented. Persons who received blood or blood components from
donors who subsequently tested positive for anti-HCV using a
licensed multiantigen assay should be notified as provided for
in
guidance issued by FDA. For specific details regarding this
notification, readers should refer to the FDA document, Guidance
for Industry. Current Good Manufacturing Practice for Blood and
Blood Components: (1) Quarantine and Disposition of Units from
Prior Collections from Donors with Repeatedly Reactive Screening
Tests for Antibody to Hepatitis C Virus (Anti-HCV); (2)
Supplemental Testing, and the Notification of Consignees and
Blood
Recipients of Donor Test Results for Anti-HCV. (This document is
available on the Internet at
.)

Blood-collection establishments and transfusion services should
work with local and state health agencies to coordinate this
notification effort. Health-care professionals should have
information regarding the notification process and HCV infection
so
that they are prepared to discuss with their patients why they
were
notified and to provide appropriate counseling, testing, and
medical evaluation. Health-education material sent to recipients
should be easy to understand and include information concerning
where they can be tested, what hepatitis C means in terms of
their
day-to-day living, and where they can obtain more information.

Persons who received a transfusion of blood or blood components
(including platelets, red cells, washed cells, and fresh frozen
plasma) or a solid-organ transplant (e.g., heart, lung, kidney,
or
liver) before July 1992. Patients with a history of blood
transfusion or solid-organ transplantation before July 1992
should
be counseled, tested, and evaluated for HCV infection.
Health-care
professionals in primary-care and other appropriate settings
routinely should ascertain their patients' transfusion and
transplant histories either through questioning their patients,
including such risk factors for transfusion as hematologic
disorders, major surgery, trauma, or premature birth, or through
review of their medical records. In addition, transfusion
services,
public health agencies, and professional organizations should
provide to the public, information concerning the need for HCV
testing in this population. Health-care professionals should be
prepared to discuss these issues with their patients and provide
appropriate counseling, testing, and medical evaluation.

Individual institutions should establish policies and
procedures for HCV testing of persons after percutaneous or
permucosal exposures to blood and ensure that all personnel are
familiar with these policies and procedures (see text box on next
page) (141). Health-care professionals who provide care to persons
exposed to HCV in the occupational setting should be knowledgeable
regarding the risk for HCV infection and appropriate counseling,
testing, and medical follow-up.

IG and antiviral agents are not recommended for postexposure
prophylaxis of hepatitis C. Limited data indicate that antiviral
therapy might be beneficial when started early in the course of HCV
infection, but no guidelines exist for administration of therapy
during the acute phase of infection. When HCV infection is
identified early, the individual should be referred for medical
management to a specialist knowledgeable in this area.

Children Born to HCV-Positive Women

Because of their recognized exposure, children born to
HCV-positive women should be tested for HCV infection (158). IG and
antiviral agents are not recommended for postexposure prophylaxis
of infants born to HCV-positive women. Testing of infants for
anti-HCV should be performed no sooner than age 12 months, when
passively transferred maternal anti-HCV declines below detectable
levels. If earlier diagnosis of HCV infection is desired, RT-PCR
for HCV RNA may be performed at or after the infant's first
well-child visit at age 1-2 months. Umbilical cord blood should not
be used for diagnosis of perinatal HCV infection because cord blood
can be contaminated by maternal blood. If positive for either
anti-HCV or HCV RNA, children should be evaluated for the presence
or development of liver disease, and those children with
persistently elevated ALT levels should be referred to a specialist
for medical management.

Routine testing is recommended only for follow-up for a
specific exposure.

Pregnant Women

Health-care professionals in settings where pregnant women are
evaluated or receive routine care should take risk histories from
their patients designed to determine the need for testing and other
prevention measures, and those health-care professionals should be
knowledgeable regarding HCV counseling, testing, and medical
follow-up.

Household (Nonsexual) Contacts of HCV-Positive Persons

Routine testing for nonsexual household contacts of
HCV-positive persons is not recommended unless a history exists of
a direct (percutaneous or mucosal) exposure to blood.

Persons for Whom Routine HCV Testing Is of Uncertain Need

For persons at potential (or unknown) risk for HCV infection,
the need for, or effectiveness of, routine testing has not been
determined.

Persons with a history of multiple sex partners or sexually
transmitted diseases.

Long-term steady sex partners of HCV-positive persons.

Recipients of Transplanted Tissue

On the basis of currently available data, risk for HCV
transmission from transplanted tissue (e.g., corneal,
musculoskeletal, skin, ova, or sperm) appears to be rare.

Intranasal Cocaine and Other Noninjecting Illegal Drug Users

Currently, the strength of the association between intranasal
cocaine use and HCV infection does not support routine testing
based solely on this risk factor.

Persons with a History of Tattooing or Body Piercing

Because no data exist in the United States documenting that
persons with a history of such exposures as tattooing and body
piercing are at increased risk for HCV infection, routine testing
is not recommended based on these exposures alone. In settings
having a high proportion of HCV-infected persons and where
tattooing and body piercing might be performed in an unregulated
manner (e.g., correctional institutions), these types of exposures
might be a risk factor for HCV infection. Data are needed to
determine the risk for HCV infection among persons who have been
exposed under these conditions.

Persons with a History of Multiple Sex Partners or STDs

Although persons with a history of multiple sex partners or
treatment for STDs and who deny injecting-drug use appear to have
an increased risk for HCV infection, insufficient data exist to
recommend routine testing based on these histories alone.
Health-care professionals who provide services to persons with STDs
should use that opportunity to take complete risk histories from
their patients to ascertain the need for HCV testing, provide
risk-reduction counseling, offer hepatitis B vaccination, and, if
appropriate, hepatitis A vaccination.

Long-Term Steady Sex Partners of HCV-Positive Persons
HCV-positive persons with long-term steady partners do not need to
change their sexual practices. Persons with HCV infection should
discuss with their partner the need for counseling and testing. If
the partner chooses to be tested and tests negative, the couple
should be informed of available data regarding risk for HCV
transmission by sexual activity to assist them in making decisions
about precautions (see section regarding counseling messages for
HCV-positive persons). If the partner tests positive, appropriate
counseling and evaluation for the presence or development of liver
disease should be provided.

Testing for HCV Infection
Consent for testing should be obtained in a manner consistent with
that for other medical care and services provided in the same
setting, and should include measures to prevent unwanted disclosure
of test results to others. Persons should be provided with
information regarding

exposures associated with the transmission of HCV, including
behaviors or exposures that might have occurred infrequently or
many years ago;

Comprehensive information regarding hepatitis C should be
provided
before testing; however, this might not be practical when HCV
testing is performed as part of a clinical work-up or when testing
for anti-HCV is required. In these cases, persons should be
informed that a) testing for HCV infection will be performed, b)
individual results will be kept confidential, and c) appropriate
counseling and referral will be offered if results are positive.

Testing for HCV infection can be performed in various settings,
including physicians' offices, other health-care facilities, health
department clinics, and HIV or other freestanding counseling and
testing sites. Such settings should be prepared to provide
appropriate information regarding hepatitis C and provide or offer
referral for additional medical care or other needed services
(e.g., drug treatment), as warranted. Facilities providing HCV
testing should have access to information regarding referral
resources, including availability, accessibility, and eligibility
criteria of local medical care and mental health professionals,
support groups, and drug-treatment centers.
The diagnosis of HCV infection can be made by detecting either
anti-HCV or HCV RNA. Anti-HCV is recommended for routine testing of
asymptomatic persons, and should include use of both EIA to test
for anti-HCV and supplemental or confirmatory testing with an
additional, more specific assay (Figure_3). Use of supplemental
antibody testing (i.e., RIBATM) for all positive anti-HCV results
by EIA is preferred, particularly in settings where clinical
services are not provided directly.

Supplemental anti-HCV testing confirms the presence of anti-HCV
(i.e., eliminates false-positive antibody results), which indicates
past or current infection, and can be performed on the same serum
sample collected for the EIA (i.e., routine serology). Confirmation
or exclusion of HCV infection in a person with indeterminate
anti-HCV supplemental test results should be made on the basis of
further laboratory testing, which might include repeating the
anti-HCV in two or more months or testing for HCV RNA and ALT
level.

In clinical settings, use of RT-PCR to detect HCV RNA might be
appropriate to confirm the diagnosis of HCV infection (e.g., in
patients with abnormal ALT levels or with indeterminate
supplemental anti-HCV test results) although RT-PCR assays are not
currently FDA-approved. Detection of HCV RNA by RT-PCR in a person
with an anti-HCV-positive result indicates current infection.
However, absence of HCV RNA in a person with an anti-HCV-positive
result based on EIA testing alone (i.e., without supplemental
anti-HCV testing) cannot differentiate between resolved infection
and a false-positive anti-HCV test result. In addition, because
some persons with HCV infection might experience intermittent
viremia, the meaning of a single negative HCV RNA result is
difficult to interpret, particularly in the absence of additional
clinical information. If HCV RNA is used to confirm anti-HCV
results, a separate serum sample will need to be collected and
handled in a manner suitable for RT-PCR. If the HCV RNA result is
negative, supplemental anti-HCV testing should be performed so that
the anti-HCV EIA result can be interpreted before the result is
reported to the patient.

Laboratories that perform HCV testing should follow the
recommended
anti-HCV testing algorithm, which includes use of supplemental
testing. Having assurances that the HCV testing is performed in
accredited laboratories whose services adhere to recognized
standards of good laboratory practice is also necessary.
Laboratories that perform HCV RNA testing should review routinely
their data regarding internal and external proficiency testing
because of great variability in accuracy of HCV RNA testing.

Prevention Messages and Medical Evaluation
HCV-specific information and prevention messages should be provided
to infected persons and individuals at risk by trained personnel in
public and private health-care settings. Health-education materials
should include a) general information about HCV infection; b) risk
factors for infection, transmission, disease progression, and
treatment; and c) detailed prevention messages appropriate for the
population being tested. Written materials might also include
information about community resources available for HCV-positive
patients for medical evaluation and social support, as appropriate.

Persons with High-Risk Drug and Sexual Practices

Regardless of test results, persons who use illegal drugs or
have high-risk sexual practices or occupations should be provided
with information regarding how to reduce their risk for acquiring
bloodborne and sexually transmitted infections or of potentially
transmitting infectious agents to others (see section regarding
primary prevention).

Negative Test Results

If their exposure was in the past, persons who test negative
for HCV should be reassured.

Indeterminate Test Results

Persons whose HCV test results are indeterminate should be
advised that the result is inconclusive, and they should receive
appropriate follow-up testing or referral for further testing (see
section regarding testing for HCV infection).

Positive Test Results

Persons who test positive should be provided with information
regarding the need for a) preventing further harm to their liver;
b) reducing risks for transmitting HCV to others; and c) medical
evaluation for chronic liver disease and possible treatment.

To protect their liver from further harm, HCV-positive persons
should be advised to

not drink alcohol;

not start any new medicines, including over-the-counter and
herbal medicines, without checking with their doctor; and

get vaccinated against hepatitis A if liver disease is
found to be present.

To reduce the risk for transmission to others, HCV-positive
persons should be advised to

not donate blood, body organs, other tissue, or semen;

not share toothbrushes, dental appliances, razors, or other
personal-care articles that might have blood on them; and

cover cuts and sores on the skin to keep from spreading
infectious blood or secretions.

HCV-positive persons with one long-term steady sex partner do
not need to change their sexual practices. They should

discuss the risk, which is low but not absent, with their
partner (If they want to lower the limited chance of
spreading HCV
to their partner, they might decide to use barrier
precautions
{e.g., latex condoms}); and

discuss with their partner the need for counseling and
testing.

HCV-positive women do not need to avoid pregnancy or
breastfeeding. Potential, expectant, and new parents should be
advised that

approximately 5 out of every 100 infants born to
HCV-infected women become infected (This occurs at the time
of
birth, and no treatment exists that can prevent this from
happening);

infants infected with HCV at the time of birth seem to do
very well in the first years of life (More studies are
needed to
determine if these infants will be affected by the
infection as
they grow older);

no evidence exists that mode of delivery is related to
transmission; therefore, determining the need for cesarean
delivery
versus vaginal delivery should not be made on the basis of
HCV
infection status;

limited data regarding breastfeeding indicate that it does
not transmit HCV, although HCV-positive mothers should
consider
abstaining from breastfeeding if their nipples are cracked
or
bleeding;

infants born to HCV-positive women should be tested for HCV
infection and if positive, evaluated for the presence or
development of chronic liver disease (see section regarding
routine
testing of children born to HCV-positive women); and

if an HCV-positive woman has given birth to any children
after the woman became infected with HCV, she should
consider
having the children tested.

Other counseling messages

HCV is not spread by sneezing, hugging, coughing, food or
water, sharing eating utensils or drinking glasses, or
casual
contact.

Persons should not be excluded from work, school, play,
child-care or other settings on the basis of their HCV
infection
status.

Involvement with a support group might help patients cope
with hepatitis C.

HCV-positive persons should be evaluated (by referral or
consultation, if appropriate) for presence or development of
chronic liver disease including

assessment for biochemical evidence of chronic liver
disease;

assessment for severity of disease and possible treatment
according to current practice guidelines in consultation
with, or
by referral to, a specialist knowledgeable in this area
(see
excerpts from NIH Consensus Statement in the following
section);
and

The NIH "Consensus Statement on Management of Hepatitis C" was
based on data available in March 1997 (133). Because of advances in
the field of antiviral therapy for chronic hepatitis C, standards
of practice might change, and readers should consult with
specialists knowledgeable in this area.

Persons Recommended for Treatment

Treatment is recommended for patients with chronic hepatitis
C who are at greatest risk for progression to cirrhosis, as
characterized by

persistently elevated ALT levels;

detectable HCV RNA; and

a liver biopsy indicating either portal or bridging fibrosis or
at least moderate degrees of inflammation and necrosis.

patients with persistent ALT elevations, but with less severe
histologic changes (i.e., no fibrosis and minimal
necroinflammatory
changes) (In these patients, progression to cirrhosis is likely
to
be slow, if at all; therefore, observation and serial
measurements
of ALT and liver biopsy every 3-5 years is an acceptable
alternative to treatment with interferon); and

patients aged less than 18 years or greater than 60 years (note
that interferon is not approved for patients aged less than 18
years).

Persons for Whom Treatment Is Not Recommended
Included are

patients with persistently normal ALT values;

patients with advanced cirrhosis who might be at risk for
decompensation with therapy;

patients who are currently drinking excessive amounts of alcohol
or who are injecting illegal drugs (treatment should be delayed
until these behaviors have been discontinued for greater than or
equal to 6 months); and

persons with major depressive illness, cytopenias,
hyperthyroidism, renal transplantation, evidence of autoimmune
disease, or who are pregnant.

identify infected persons who can be counseled and referred for
medical follow-up.

Various surveillance approaches are required to achieve these
objectives because of limitations of diagnostic tests for HCV
infection, the number of asymptomatic patients with acute and
chronic disease, and the long latent period between infection and
chronic disease outcome.

Surveillance for Acute Hepatitis C

Surveillance for acute hepatitis C -- new, symptomatic
infections -- provides the information necessary for determining
incidence trends, changing patterns of transmission and persons at
highest risk for infection. In addition, surveillance for new cases
provides the best means to evaluate effectiveness of prevention
efforts and to identify missed opportunities for prevention. Acute
hepatitis C is one of the diseases mandated by the Council of State
and Territorial Epidemiologists (CSTE) for reporting to CDC's
National Notifiable Diseases Surveillance System. However,
hepatitis C reporting has been unreliable to date because most
health departments do not have the resources required for case
investigations to determine if a laboratory report represents acute
infection, chronic infection, repeated testing of a person
previously reported, or a false-positive result. Historically, the
most reliable national data regarding acute disease incidence and
transmission patterns have come from sentinel surveillance (i.e.,
sentinel counties study of acute viral hepatitis). As hepatitis C
prevention and control programs are implemented, federal, state,
and local agencies will need to determine the best methods to
effectively monitor new disease acquisition.

Laboratory Reports of Anti-HCV-Positive Tests

Although limitations exist for the use of anti-HCV-positive
laboratory reports to identify new cases and to monitor trends in
disease incidence, they potentially are an important source from
which state and local health departments can identify infected
persons who need counseling and medical follow-up. Development of
registries of persons with anti-HCV-positive laboratory results
might facilitate efforts to provide counseling and medical
follow-up and these registries could be used to provide local,
state, and national estimates of the proportion of persons with HCV
infection who have been identified. If such registries are
developed, the confidentiality of individual identifying
information should be ensured according to applicable laws and
regulations.

Serologic Surveys

Serologic surveys at state and local levels can characterize
regional and local variations in prevalence of HCV infection,
identify populations at high risk, monitor trends, and evaluate
prevention programs. Existing laboratory-based reporting of
HCV-positive test results cannot provide this information because
persons who are tested will not be representative of the population
as a whole, and certain populations at high risk might be
underrepresented. Thus, data from newly designed or existing
serologic surveys will be needed to monitor trends in HCV infection
and evaluate prevention programs at state and local levels.

Surveillance for Chronic Liver Disease

Surveillance for HCV-related chronic liver disease can provide
information to measure the burden of disease, determine natural
history and risk factors, and evaluate the effect of therapeutic
and prevention measures on incidence and severity of disease. Until
recently, no such surveillance existed, but a newly established
sentinel surveillance pilot program for physician-diagnosed chronic
liver disease will provide baseline data and a template for a
comprehensive sentinel surveillance system for chronic liver
disease. As the primary source of data regarding the incidence and
natural history of chronic liver disease, this network will be
pivotal for monitoring the effects of education, counseling, other
prevention programs, and newly developed therapies on the burden of
the disease.

FUTURE DIRECTIONS

To prevent chronic HCV infection and its sequelae, prevention
of new HCV infections should be the primary objective of public
health activities. Achieving this objective will require the
integration of HCV prevention and surveillance activities into
current public health infrastructure. In addition, several
questions concerning the epidemiology of HCV infection remain, and
the answers to those questions could change or modify primary
prevention activities. These questions primarily concern the
magnitude of the risk attributable to sexual transmission of HCV
and to illegal noninjecting-drug use.

Identification of the large numbers of persons in the United
States with chronic HCV infection is resource-intensive. The most
efficient means to achieve this identification is unknown, because
the prevention effectiveness of various implementation strategies
has not been evaluated. However, widespread programs to identify,
counsel, and treat HCV-infected persons, combined with improvements
in the efficacy of treatment, are expected to lower the morbidity
and mortality from HCV-related chronic liver disease substantially.
Monitoring the progress of these activities to determine their
effectiveness in achieving a reduction in HCV-related chronic
disease is important.

Dufour MC. Chronic liver disease and cirrhosis. In Everhart
JE,
ed. Digestive diseases in the United States: epidemiology and
impact. US Department of Health and Human Services, Public
Health
Service, National Institutes of Health, National Institute of
Diabetes and Digestive and Kidney Diseases. Washington, DC: US
Government Printing Office, 1994; NIH publication no. 94-1447,
615-45.

US Department of Health and Human Services. Medical advice for
persons who inject illicit drugs. HIV Prevention Bulletin.
CDC,
Health Resources & Services Administration, National Institute
on
Drug Abuse of the National Institutes of Health, and the
Center for
Substance Abuse and Mental Health Services Administration, May
1997.

Gostin LO, Lazzarini Z, Jones TS, Flaherty K. Prevention of
HIV/AIDS and other blood-borne diseases among injection drug
users:
a national survey on the regulation of syringes and needles.
JAMA
1997;277:53-62.

*
Sentinel counties viral hepatitis surveillance system identifies
all persons w
symptomatic acute viral hepatitis reported through stimulated
passive surveillan
participating county health departments (four during 1982-1995 and
six during 19
These counties are demographically representative of the U.S.
population. Serum
from reported cases are tested for all viral hepatitis markers, and
case-patient
interviewed extensively for risk factors for infection.

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